Urinary Excretion Of Radioactivity Research Articles

Comparison of [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is preferable for PRRT?

Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [(177)Lu-DOTA(0),Tyr(3)]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [(177)Lu-DOTA(0),Tyr(3)]octreotide ((177)Lu-DOTATOC) and [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-DOTATATE), to see which peptide should be preferred for PRRT with (177)Lu. In the same patients, 3,700 MBq (177)Lu-DOTATOC and 3,700 MBq (177)Lu-DOTATATE was administered in separate therapy sessions. Amino acids were co-administered. Whole-body scanning was performed on days 1, 4 and 7 post therapy. Blood and urine samples were collected. We calculated residence times for tumours, spleen and kidneys. All patients had longer residence times in spleen, kidneys and tumours after use of (177)Lu-DOTATATE (p=0.016 in each case). Comparing (177)Lu-DOTATATE with (177)Lu-DOTATOC, the mean residence time ratio was 2.1 for tumour, 1.5 for spleen and 1.4 for kidneys. Dose-limiting factors for PRRT are bone marrow and/or kidney dose. Although the residence time for kidneys was longer when using (177)Lu-DOTATATE, the mean administered dose to tumours would still be advantageous by a factor of 1.5, assuming a fixed maximum kidney dose is reached. Plasma radioactivity after (177)Lu-DOTATATE was comparable to that after (177)Lu-DOTATOC. Urinary excretion of radioactivity was comparable during the first 6 h; thereafter there was a significant advantage for (177)Lu-DOTATOC. (177)Lu-DOTATATE had a longer tumour residence time than (177)Lu-DOTATOC. Despite a longer residence time in kidneys after (177)Lu-DOTATATE, tumour dose will always be higher. Therefore, we conclude that the better peptide for PRRT is octreotate.

Pharmacokinetics and Disposition of Silodosin (KMD-3213)

After a single oral dose of silodosin in male rats, male dogs and healthy human male volunteers, C(max) occurred within about 2 h, indicating rapid absorption. The elimination half-life was about 2 h in rat and dog, but 4.7 h (fasted) and 6.0 h (non-fasted) in humans. Absolute bioavailability values in rat, dog and human were about 9, 25 and 32%, respectively. In rat and dog, total blood clearance was almost equivalent to the hepatic blood flow, but that in human was low (20%), demonstrating a large species difference in hepatic clearance. In each species, the apparent volume of distribution exceeded the volume of total body water. After an oral dose of (14)C-silodosin to male rats, radioactivity was rapidly and widely distributed to most tissues. The highest concentrations outside the gastrointestinal tract were found in liver and kidney, with only low concentrations in brain tissues. The in vitro plasma protein binding of silodosin was about 80% in rat and dog, and 95.6% in humans, with alpha(1)-acid glycoprotein (AGP) contributing to the binding profile. Silodosin was found to be a dual substrate for CYP3A4 and p-glycoprotein. In human plasma, two major metabolites generated by UDP-glucuronosyltransferase (UGT; UGT2B7) and alcohol/aldehyde dehydrogenase (ADH/ALDH) were found, but no glucuronide conjugates were detected in rat or dog plasma. After a single oral dose of (14)C-silodosin in rat, dog and human, the urinary excretion of radioactivity was 15-34%, with that of unchanged silodosin being less than 4%. The radioactivity was predominantly excreted via the feces.

Carbidopa pretreatment improves image interpretation and visualisation of carcinoid tumours with 11C-5-hydroxytryptophan positron emission tomography

Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) as tracer is a promising imaging instrument in the management of patients with neuroendocrine tumours (NETs). However, high radioactivity concentrations in the urinary collecting system sometimes produce image reconstruction artefacts that can make detection of small NETs difficult. As a means to decrease urinary excretion of radioactivity and thereby improve image quality, we examined the effect of pretreatment with carbidopa (CD), a peripheral inhibitor of aromatic amino acid decarboxylase (AADC), which converts 5-HTP to serotonin (5-hydroxytryptamine, 5-HT). Six patients with midgut carcinoid metastases were examined with 11C-5-HTP PET before and 1 h after oral administration of 100 or 200 mg of CD. There was a fourfold significant reduction of tracer uptake in the urinary collecting system after CD administration (p=0.0277, n=6), with a mean standard uptake value (SUV) of 155+/-195 before CD and 39+/-14 after CD. In tumour lesions there was a significant increase in SUV after CD administration (p<0. 0001, n=18), with a mean SUV of 11+/-3 before CD and 14+/-3 after CD. There was no difference between the doses (100 and 200 mg) of CD in this respect. In all patients, image interpretation and tumour detection were markedly improved after CD administration. We conclude that CD premedication improves 11C-5-HTP PET image quality and facilitates detection of NET lesions. Because of the similarity of metabolic pathways, this method could probably be applied to improve PET imaging using other tracers like 18F-DOPA and 11C-DOPA.

METABOLISM OF MYOSMINE IN WISTAR RATS

The alkaloid myosmine is present not only in tobacco products but also in various foods. Myosmine is easily nitrosated, yielding 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) and the esophageal tobacco carcinogen N'-nitrosonornicotine. Due to its widespread occurrence, investigations on the metabolism and activation of myosmine are needed for risk assessment. Therefore, the metabolism of myosmine has been studied in Wistar rats treated with single oral doses of [pyridine-5-3H]myosmine at 0.001, 0.005, 0.5, and 50 micromol/kg body weight. Oral administration was achieved by feeding a labeled apple bite. Radioactivity was completely recovered in urine and feces within 48 h. At the two lower doses, 0.001 and 0.005 micromol/kg, a higher percentage of the radioactivity was excreted in urine (86.2 +/- 4.9% and 88.9 +/- 1.7%) as compared with the higher doses, 0.5 and 50 micromol/kg, where only 77.8 +/- 7.3% and 75.4 +/- 6.6% of the dose was found in urine. Within 24 h, urinary excretion of radioactivity was nearly complete with less than 4% of the total urinary output appearing between 24 and 48 h. The two major metabolites accounting for >70% of total radioactivity in urine were identified as 3-pyridylacetic acid (20-26%) and 4-oxo-4-(3-pyridyl)butyric acid (keto acid, 50-63%) using UV-diode array detection and gas chromatography-mass spectrometry measurements. 3-Pyridylmethanol (3-5%), 3'-hydroxymyosmine (2%) and HPB (1-3%) were detected as minor metabolites. 3'-Hydroxymyosmine is exclusively formed from myosmine and therefore might be used as a urinary biomarker for myosmine exposure in the future.

Identification of metabolites of [14C]zonampanel, an α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist, following intravenous infusion in healthy volunteers

This study determined the pharmacokinetics, metabolism and excretion of an α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist zonampanel monohydrate (YM872) after intravenous infusion of [14C]YM872 at 1 mg kg−1 h−1 for 2 h to four healthy male volunteers. Mean pharmacokinetic parameters of unchanged YM872 were 0.78 h for terminal half-life, 25.9 l h−1 for total clearance, 22.9 l h−1 for renal clearance, and 15.6 l for volume of distribution at steady-state. Urinary excretion of radioactivity accounted for 94.9% of the dose, and faecal excretion for only 0.5% of the dose. Measurement of YM872 concentrations by a high-performance liquid chromatography (HPLC)-ultraviolet method and radiometric HPLC metabolite profiling revealed that almost all of [14C]YM872 was excreted unchanged in the urine and that unchanged [14C]YM872 was the major circulating [14C] component in the plasma. Two minor metabolites, H1 and H2, detected in the urine and identified as the same chemical structures as those of the rat urinary metabolites, have a hydroxyamino group and an amino group, respectively, which were probably formed by reduction of the nitro group of YM872. These results show that virtually all of the administered YM872 remains unchanged, with urinary excretion representing the major elimination pathway. The high renal clearance implies tubular secretion of this drug.

Intrinsic factor studies: II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B 12

The simultaneous oral administration of normal human gastric juice and small quantities of vitamin B12 results in hematopoiesis in patients with pernicious anemia in relapse, while oral vitamin B12 alone in similar amounts is usually ineffective. 1 Berk L. Castle W.B. Welch A.D. Heinle R.W. Anker R. Epstein M. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. X. activity of vitamin B12 as food (extrinsic) factor. N Engl J Med. 1948; 239: 911 Google Scholar , 2 Schilling R.F. Harris J.W. Castle W.B. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. XIII. Hematopoietic activity of (vitamin B12). Blood. 1951; 6: 228 Google Scholar , 3 Ungley C.C. Absorption of vitamin B12 in pernicious anemia. BMJ. 1950; 2: 905 Google Scholar , 4 Hall B.E. Morgan E.H. Campbell D.C. Oral administration of vitamin B12 in pernicious anemia. I. Presence of intrinsic factor in Berkefeld-filtered pooled human gastric juice: Preliminary report, Proc Staff Meet. Mayo Clin. 1949; 24: 99 Google Scholar , 8 Hall Byron E. Studies on the nature of the intrinsic factor of castle. BMJ. 1950; 2: 585 Google Scholar The hematopoietic activity of intravenously administered vitamin B12 was not enhanced by the simultaneous intravenous administration of sterile Berkefeld filtered gastric juice in amounts known to be active as intrinsic factor when given orally. 5 Wallerstein R.O. Harris J.W. Schilling R.F. Castle W.B. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. XV. Hematopoietic effects of simultaneous intravenous and of simultaneous or serial oral administration of intrinsic factor in vitamin B12. J Lab Clin Med. 1953; 41: 363 Google Scholar Vitamin B12 by parenteral injection regularly corrects the hematologic abnormalities and arrests the neurologic disorder in pernicious anemia. Heinle and associates 6 Heinle R.W. Welch A.D. Scharf V. Meacham G.C. Prusoff W.H. Studies of excretion (and absorption) of Co60-labeled vitamin B12 in pernicious anemia. Trans Assoc Am Phys. 1952; 65: 214 Google Scholar have reported that the fecal exeretion of radioactivity in four pernicious anemia patients receiving 0.5 μg of radioactive vitamin B12 (B12Co60) by mouth was definitely greater than in normal subjects. They reported that the simultaneous oral administration of an intrinsic factor preparation and B12Co60 in three pernicious anemia patients was followed by a definite reduction of fecal radioactivity. The simplest interpretation of the above information is that the function of intrinsic factor is to promote the absorption of vitamin B12 from the intestinal tract.

Oral absorption, metabolism and excretion of 1-phenoxy-2-propanol in rats

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers.2. Rats were administered a single oral dose of 10 or 100 mg kg−1 14C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0–12, 12–24 and 24–48 h and faeces at 0–24 and 24–48 h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS.3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 ± 5% of the low and 96 ± 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12 h after dosing; 85 ± 2% of the low and 90 ± 1% of the high dose. Total faecal excretion remained < 10%. Rats eliminated the entire administered dose within 48 h after dosing; recovery of the administered dose ranged from 100 to 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulphate, glutathione) with very low levels (< 2%) of hydroquinone (glucuronide), conjugates of parent compound (glucuronide, sulphate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol in non-acid-hydrolysed urine. In acid-hydrolysed urine, 61% of the dose was identified as phenol and 13% as 1-phenoxy-2-propanol. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolysed urine may have arisen from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates.4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.

Metabolism and disposition of gemfibrozil in Wistar and multidrug resistance-associated protein 2-deficient TR− rats

1. The roles of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 up-regulation were evaluated on the metabolism and disposition of gemfibrozil.2. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CLint) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR− rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CLint for glucuronidation was similar in both strains.3. The biliary excretion of intravenously administered [14C]gemfibrozil was significantly impaired in TR− rats compared with Wistar rats (22 versus 93% of the dose excreted as the acyl glucuronides over 72 h). Additionally, the extent of urinary excretion of radioactivity was much higher in TR− than in Wistar rats (78 versus 2.6% of the dose).4. There were complex time-dependent changes in the total radioactivity levels and metabolite profiles in plasma, liver and kidney, some of which appeared to be related to the up-regulation of Mrp3.5. Overall, it was demonstrated that alterations in the expression of the transporters Mrp2 and Mrp3 significantly affected the excretion as well as the secondary metabolism and distribution of [14C]gemfibrozil.

Metabolic distribution of radioactivity in Sprague–Dawley rats and B6C3F1 mice exposed to 1,3-[2,3- 14C]–butadiene by whole body exposure

The uptake of 1,3-[2,3- 14C]–butadiene and its disposition, measured as radioactivity in urine, faeces, exhaled volatiles and CO 2 during and following 6 h whole body exposure to 20 ppm butadiene has been investigated in male Sprague–Dawley rats and B6C3F1 mice. Whilst there were similarities between the two species, the uptake and metabolic distribution of butadiene were somewhat different for rats and mice. The major differences observed were in the urinary excretion of radioactivity and in the exhalation of 14C–CO 2. After 42 h from the start of exposure, 51.1% of radioactivity was eliminated in rat urine compared with 39.5% for mouse urine. 34.9% of the recovered radioactivity was exhaled by rats as 14C–CO 2, compared with 48.7% by mice. Excretion of radioactivity in faeces was similar for both species (3.8% for rats and 3.4% for mice). The tissue concentrations of 14C–butadiene equivalents measured in liver, testes, lung and blood of exposed mice were 0.493, 0460, 0.457, and 1.626 nmol/g tissue, respectively. The values for the corresponding rat tissues were 0.869, 0.329, 0.457, and 1.626 nmol butadiene equivalents/g tissue, respectively. For rats, 6.2% of recovered radioactivity (0.288 nmol butadiene equivalents/g tissue) was retained in carcasses whereas for mice the amount was 3.6% (0.334 nmol butadiene equivalents/g tissue). There were also some significant differences between the metabolic conversion of 1,3-[2,3- 14C]–butadiene and excretion by mice following the 20 ppm whole body exposure compared to previously reported data for nose-only exposure to 200 ppm butadiene [Richardson et al., Toxicol. Sci. 49 (1999) 186]. The main difference between the high- and low-exposure studies was in the exhalation of 14C–CO 2. At the 200 ppm exposure, 40% of the radioactivity was exhaled as 14C–CO 2 by rats whereas 6% was measured by this route for mice. The proportional conversion of butadiene to CO 2 by mice was significantly greater at the low exposure concentration compared with that reported for the higher concentration. This shift was not observed for rats. The difference between species could be caused by a saturation of metabolism in mice between 20 and 200 ppm for the pathways leading to CO 2. Restraint or error in collection of CO 2 in the 200 ppm study could also be factors.

Some new aspects of 17α-estradiol metabolism in man

17α-Estradiol (1,3,5(10)-estratriene-3,17α-diol) together with a tracer dose of the tritium-labeled compound was administered orally and sublingually to male volunteers. The serum concentrations of 17α-estradiol (free and liberated by enzymatic hydrolysis) were quantified by GC/MS, and the serum total radioactivity and urinary radioactivity excretion were determined. After oral administration, 17α-estradiol was rapidly and intensively conjugated; only tiny quantities of the free steroid (<1% of total) appeared in serum. Sublingual administration resulted in temporary (up to 3 h p.a.) higher serum levels of the free compound. The metabolite patterns obtained by TLC of extracts from serum and urine demonstrated that 17α-estradiol is the subject of a poor phase I metabolism in man. A great discrepancy was found in the serum concentrations of 17α-estradiol (free+conjugated) determined by GC/MS and the serum radioactivity expressed in 17α-estradiol equivalents. By TLC analysis of the steroid conjugates extracted from serum, various 17α-estradiol conjugate peaks were found. By enzymatic hydrolysis with β-glucuronidase/aryl sulfatase from Helix pomatia they were only partially cleaved. Thus, the difference between the serum radioactivity and the 17α-estradiol levels determined by GC/MS had to be attributed to an incomplete conjugate hydrolysis. It has been shown with the synthesized 17α-estradiol sulfate conjugates that only the 3-sulfate is cleaved by enzymatic hydrolysis, whereas the 17-sulfate group resists enzymatic hydrolysis. The methanolysis procedure (acetyl chloride in MeOH) has proved to be an efficient method for cleaving both the 3-sulfate group and the 17-sulfate group. In contrast to the 17α-estradiol conjugates in serum, the urinary conjugates were intensively split by the enzyme preparation. From this, it has to be concluded that the serum conjugates were deconjugated and newly reconjugated before urinary excretion.

Disability

The urinary excretion of radioactivity has been measured in man following intravenous injection of 400 mg of [8-14C]proxyphylline. Of the radioactive dose, 95% was recovered in urine 3 days after...

Metabolic fate of (-)-[4-(3)H]epigallocatechin gallate in rats after oral administration.

After oral administration of [4-(3)H]EGCg to rats, the radioactivity in blood, major tissues, urine, and feces was measured over time. The radioactivity in blood and most tissues remained low for 4 h postdose, began to increase after 8 h, peaked at 24 h, and then decreased. Major urinary excretion of radioactivity occurred in the 8-24 h period, and the cumulative radioactivity excreted by 72 h was 32.1% of the dose. The radioactivity in the feces was 35.2% of the dose within 72 h postdose. In the case of rats pretreated with antibiotics (antibiotic-pretreated rats), the radioactivity levels of the blood and urine were definitely lower than those in rats not pretreated with antibiotics (normal rats). The radioactivity recovered in the antibiotic-pretreated rat urine was estimated to be only (1)/(100) of that in the normal rat urine. These results clearly demonstrated that the radioactivity detected in the blood and urine of normal rats mostly originated from degradation products of EGCg produced by intestinal bacteria. Furthermore, a main metabolite in the normal rats was purified and identified as 5-(5'-hydroxyphenyl)-gamma-valerolactone 3'-O-beta-glucuronide (M-2). In feces of the normal rats, EGC (40.8% of the fecal radioactivity) and 5-(3',5'-dihydroxyphenyl)-gamma-valerolactone (M-1, 16.8%) were detected. These results suggested that M-1 was absorbed in the body after degradation of EGCg by intestinal bacteria, yielding M-1 with EGC as an intermediate. Furthermore, M-2 was thought to be formed from M-1 in the intestinal mucosa and/or liver, then to enter the systemic circulation, and finally to be excreted in the urine. Taking into account all of the above findings, a possible metabolic route of EGCg orally administered to rats is proposed.

The influence of co-exposure to dimethyldithiocarbamate on butadiene metabolism

Treatment of rats and mice with a single oral dose of dimethyldithiocarbamate (DMDTC; 250 mg/kg) had a marked effect on hepatic CYP2E1 and aldehyde dehydrogenase activities, measured in vitro, for up to 24 h after dosing. The same treatment did not affect CYP2A6, glutathione S-transferase, epoxide hydrolase, alcohol dehydrogenase activities or hepatic glutathione levels. As a consequence of the loss of CYP2E1 activity, butadiene metabolism in liver fractions from DMDTC treated rats and mice was markedly reduced, as was the metabolism of the mono-epoxide to the di-epoxide in mouse liver. The conversion of the mono-epoxide to the diol by epoxide hydrolases was not affected by DMDTC treatment. Urinary excretion of radioactivity, following dosing with DMDTC and exposure to 200 ppm C-14 butadiene for 6 h, was markedly reduced in rats, but increased in mice. The profiles of urinary metabolites were qualitatively similar from mice exposed to butadiene to those exposed after dosing with DMDTC. In the rat, pre-dosing with DMDTC resulted in the formation of three additional urinary metabolites following exposure to butadiene. Overall, DMDTC appears to impact qualitatively and quantitatively on the metabolism of butadiene. The nature and full significance of these changes has yet to be characterised.

Radioiodinated N-(2-diethylaminoethyl)benzamide derivatives with high melanoma uptake: structure-affinity relationships, metabolic fate, and intracellular localization.

Several radioiodinated N-(dialkylaminoalkyl)benzamides have been used for planar scintigraphy and single-photon emission computed tomography (SPECT) of melanoma metastases. In a quest for improved melanoma uptake and tissue selectivity, structure-activity studies for N-(2-diethylaminoethyl)benzamides with variation of phenyl substituents were performed using C57Bl/6 mice bearing B16 melanoma. Compounds 2 (4-amino-5-bromo-N-(2-diethylaminoethyl)-3-[(131)I]iodo-2-methoxybenz amide) and 6 (4-acetamido-N-(2-diethylaminoethyl)-5-[(131)I]iodo-2-methoxybenzamid e) showed at 6 h post iv injection, for example, melanoma uptake of 16.6 and 23.2% ID/g, respectively (mean values, n = 3). Uptake was 3-5 times higher (P < 0.01) than observed with benzamides known from the literature and was probably facilitated by the relatively slow urinary excretion of 2 or 6. In contrast, analogues lacking either the MeO, Ac, AcNH, or Br substituents exhibited reduced tumor uptake and high urinary excretion of radioactivity in various benzamide metabolites. Uptake of radioiodinated benzamides in B16 melanoma is not mediated by a specific mechanism such as sigma-receptor binding. 2 and 6 exhibited similar melanoma uptake values but quite different sigma(1)-receptor affinities of K(i) = 0.278 +/- 0.018 and 5.19 +/- 0.40 microM, respectively. Uptake studies with IMBA (N-(2-diethylaminoethyl)-3-[(131)I]iodo-4-methoxybenzamide) or BZA (N-(2-diethylaminoethyl)-4-[(131)I]iodobenzamide) showed that with increasing dose of unlabeled compound the measured uptake of label was unchanged (IMBA) or even enhanced (BZA) while receptor binding of label decreased. Differential and equilibrium density-gradient centrifugation revealed that most of the radioactivity from labeled IMBA was associated with fractions containing melanin granules. Thus, structure-activity studies indicate that blood clearance rates and metabolic stability are the main determinants for benzamide uptake in melanoma. The high uptake and slow clearance of 6 offer considerable potential for melanoma imaging in patients, and this compound may also prove to be useful for radionuclide therapy.

Pharmacokinetics of [14C]Genistein in the Rat: Gender-Related Differences, Potential Mechanisms of Biological Action, and Implications for Human Health

Mass balance, plasma pharmacokinetics, tissue distribution, and metabolism of [14C]genistein were investigated in male and female rats (n = 5) following an oral dose of [14C]genistein (4 mg kg−1) to determine potential sites and mechanisms of biological action. Mean total excretion of radioactivity in urine and feces for both sexes was 66 and 33% of the dose respectively at 166 h after administration. Mean and maximal concentrations of radioactivity in plasma were significantly (p < 0.02) higher in male than female rats, with half-lives of 12.4 and 8.5 h, respectively. The concentration of radioactivity was significantly (p < 0.002) higher in liver from females than males and in reproductive (vagina, uterus, ovary, and prostate) compared with other peripheral organs. Analysis of plasma extracts by radio-HPLC-MS indicated that the predominant metabolites were genistein glucuronides, 4-hydroxyphenyl-2-propionic acid, and trace amounts of parent compound (<5%). Radioactive residues in uterus and prostate were predominantly parent compound and 4-hydroxyphenyl-2-propionic acid, respectively. Significantly (p < 0.05) increased retention of [14C]genistein or metabolites was associated with reproductive organs, such as vagina, uterus, ovary, and prostate, likely to contain relatively high concentrations of estrogen receptors or binding proteins compared with other peripheral tissues. Factors liable to influence bioavailability of biologically active genistein or metabolites, such as dietary intake, warrant further investigation to determine the risks or benefits for different consumer groups of phytoestrogen-containing foods.

Studies on the Metabolic Fate of TA-510, a Hepatic Anti-inflammatory Agent. (1). Blood Concentration, Distribution and Excretion in Bats and Dogs.

新規肝機能改善薬として開発されたTA-510の体内動態を明らかにする目的で，14C-TA-510を雄性ラットおよび雄性イヌに単回経口(30mg/kg)および単回静脈内(3mg/kg)投与した時の血中濃度推移，分布および排泄について検討した．1．14C-TA-510をラットおよびイヌに経口あるいは静脈内投与した時の尿中放射能排泄率の比から算出されたTA-510の消化管吸収率は，それぞれ約80%および100%であった．2．経口投与時において，ラット血漿中未変化体のCmaxおよびAUCはイヌに比べてそれぞれ約50倍および80倍低い値を示した．ラット血漿中の総放射能濃度のAUCに対する未変化体濃度のAUCの比率は僅か2%と少なく，TA-510は雄性ラットにおいて初回通過代謝を受けることが示唆された．3．ラット経口投与時において，消化管以外の多くの組織中の放射能は投与後6時間で最も高く分布し，血液より高濃度の放射能が標的臓器である肝臓の他に腎臓にも認められた．また，血液と同程度の放射能が肺と皮膚に認められた．脳，脾臓および精巣をはじめとした他の組織への放射能の分布は極めて少なかった．その後，組織中放射能は経時的に減少し，投与後72時間では消化管内容物と肝臓に僅かに認められたのみであった．4．ラットに経口投与後の72時間までに投与した放射能の27.5%および68.9%が尿および糞中に排泄された．また，ラットに経口投与後の48時間までの胆汁および尿中の累積放射能排泄率はそれぞれ72.2%および5.5%であった．体外に排泄された胆汁を再び十二指腸内に投与した際に，投与放射能の35.9%が吸収された．一方，イヌにおいて経口投与後72時間までの尿および糞中に回収された放射能は，それぞれ51.4%および44.7%であった．

Urinary and Biliary Metabolic Patterns of Chlorothalonil in Germ-Free and Conventional Rats

The metabolic fate of chlorothalonil, a broad spectrum fungicide that is known to be metabolized via glutathione conjugation, was examined through the analysis of urine and bile metabolites. The role of digestive microflora in the metabolism of chlorothalonil was assessed by comparing the metabolic patterns in germ-free and conventional rats. Low urinary and biliary excretion of radioactivity was observed in both conventional and germ-free rats. However, the urinary excretion of radioactivity was higher in conventional than in germ-free rats. Radio-HPLC analysis of urine and bile showed a complex metabolic profile in both conventional and germ-free rats. Methylthio metabolites of chlorothalonil were determined in ethyl acetate extracts of urine and bile of conventional and germ-free rats. These metabolites were excreted in a higher amount in the urine of conventional rats than in the urine of germ-free rats. This study shows the complexity of chlorothalonil metabolism and the role of the digestive microflora in chlorothalonil metabolism.

Metabolism and disposition of GTS-21, a novel drug for Alzheimer's disease

1. GTS-21, a novel drug for Alzheimer's disease, is currently under clinical development. In the current study, the metabolism and disposition of GTS-21 have been evaluated in rat and dog after single oral and intravenous administration. 2. Following oral administration of [14C]GTS-21 to rat, radioactivity was primarily excreted in the faeces (67%) via the bile with possible enterohepatic circulation. Urinary excretion of radioactivity in rat and dog was 20 and 19% respectively. 3. GTS-21 was rapidly and extensively absorbed after oral administration and rapidly cleared from plasma. The maximum concentration ratio of GTS-21 to total radioactivity in plasma was low, indicating first-pass or pre-systemic biotransformation. 4. In rat, GTS-21 showed linear pharmacokinetics over doses ranging from 1 to 10 mg/kg with an absolute bioavailability of 23%. In dog, the absolute bioavailability was 27% at an oral dose of 3 mg/kg. 5. GTS-21 was O-demethylated to yield compounds that were then subject to glucuronidation. Three of the metabolites in rat urine were isolated and characterized as 4-OH-GTS-21, 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. The major urinary metabolites were 4-OH-GTS-21 glucuronide and 2-OH-GTS-21 glucuronide. 6. In vitro chemical inhibition of cytochrome P450 in human liver microsomes indicated that CYP1A2 and CYP2E1 were the isoforms primarily responsible for the O-demethylation of GTS-21, with some contribution from CYP3A.

Absorption, Distribution and Excretion of OPB-2045 following a Single Subcutaneous Administration to Rats.

Examination was made of the absorption, distribution and excretion of radioactivity in SpragueDawly rats following a single subcutaneous administration of 14C-labeled OPB-2045 at 1 mg/kg, and the following results were obtained: 1. Serum concentrations of radioactivity were maximum (Cmax) of 0.032-0.033 μg eq./ml at 1 hr after administration in male and female rats. Radioactivity half-life in serum was 77.0 hr as determined at 48 hr to 168 hr postdosing in male and female rats. The area under the serum concentration-time curve (AUC0→∞) was 0.75 to 0.78 μg eq.·hr/ml. Radioactivity in blood cells accounted for 31.9-77.9% of total radioactivity in the blood. Radioactivity in the blood exceeded that in the serum. AUC0→∞ in the blood was 1.5 to 2 times that of the serum. 2. Radioactivity was highest in the pituitary gland, followed by the thyroid, adrenal glands, lungs and kidneys in male rats 1 hr postdosing. In tissues, it was 10 to 26 times higher than in the blood. At 8 and 24 hr postdosing, radioactivity in adrenal glands was extremely high, and 100 to 200 times that in the blood. At 72 and 168 hr postdosing, radioactivity was high in the adrenal and pituitary glands and kidneys. Its tissue distribution in female rats was essentially the same as in male rats. 3. Urinary and fecal excretion of radioactivity was 17.2-20.8% and 68.4-71.2% of the administered doses, respectively, with 9.1-9.3% remaining in the carcass at 168 hr postdosing. 4. Biliary and urinary excretion of radioactivity at 24 hr postdosing accounted for 34.1% and 14.2% the administered doses, respectively, in male rats whose bile ducts had been cannulated.

Absorption, distribution, metabolism and excretion of 14C-labelled enantiomers of the calcium channel blocker benidipine after oral administration to rat

1. Each of the 14C-labelled optical isomers of benidipine, a new calcium antagonist, was separately administered orally to the male rat at a dose of 0·5 or 1 mg/kg. The absorption, distribution, metabolism and excretion of the 14C-labelled optical isomers were investigated. 2. Plasma concentrations of radioactivity after administration of the (−)-α isomer were higher than those after administration of the (+)-α isomer. 3. The highest radioactivity was found in liver and high levels of radioactivity were found in the kidney, adrenal gland and lung after administration of the (+)- or (−)-α isomers of benidipine. Up to 72 h, the tissue concentration of radioactivity fell from 1·4 to 9·2% of the highest level in each tissue for the (+)-α isomer and from 1·8 to 13·0% for the (−)-α isomer. 4. The ratios of the area under the time-curve of each tissue concentration to that of the corresponding plasma concentration were almost equal after the separate administrations of both isomers. 5. The dominant urinary and biliary metabolic pathways of the (+)-isomer were the hydrolysis of 1-benzyl 3-piperidylester followed by the oxidation of the dihydropyridine ring and N-dealkylation followed by hydrolysis of the methylester. Those of the (−)isomer were the hydrolysis of 1-benzyl 3-piperidylester followed by the oxidation of dihydropyridine ring and of the oxidation methyl group, N-dealkylation followed by hydrolysis of the methylester,decarboxylation and glucuronidation of the piperidyl moiety after the oxidation of the dihydropyridine ring. 6. The cumulative excretion of radioactivity in urine and faeces up to 72 h after administration of the (+)-α isomer was 8·8 and 90·7% of the dose respectively. The corresponding values of the (+)-α isomer were 19·7 and 72·9% of the dose respectively. 7. The excretion of radioactivity in bile up to 48 h after administration of the (+)- and (−)-α isomer was 42·1 and 46·7% of the dose respectively.